The present invention relates to an apparatus for transcranial magnetic brain stimulation. The invention also relates to methods for localizing and characterizing speech arrest, and for treatment of depression using transcranial magnetic stimulation.
The Magnetic Stimulator Apparatus
Magnetic stimulation of neurons has been heavily investigated over the last decade. Almost all magnetic stimulation work has been done in vivo. The bulk of the magnetic stimulation work has been in the area of brain stimulation.
Cohen has been a rather large contributor to this field of research (See e.g., T. Kujirai, M. Sato, J. Rothwell, and L. G. Cohen, xe2x80x9cThe Effects of Transcranial Magnetic Stimulation on Median Nerve Somatosensory Evoked Potentialsxe2x80x9d, Journal of Clinical Neurophysiology and Electro Encephalography, Vol. 89, No. 4, 1993, pps. 227-234, the disclosure of which is fully incorporated herein by reference.) This work has been accompanied by various other research efforts including that of Davey, et al. and that of Epstein (See, K. R. Davey, C. H. Cheng, C. M. Epstein xe2x80x9cAn Alloyxe2x80x94Core Electromagnet for Transcranial Brain Stimulationxe2x80x9d, Journal of Clinical Neurophysiology, Volume 6, Number 4, 1989; and, Charles Epstein, Daniel Schwartzberg, Kent Davey, and David Sudderth, xe2x80x9cLocalizing the Site of Magnetic Brain Stimulation in Humansxe2x80x9d, Neurology, Volume 40, April 1990, pps. 666-670, the disclosures of which are fully incorporated herein by reference).
Generally, the magnetic stimulation research has used air type coils in their stimulators. These coils are so named due to the fact that they lack a magnetic core. A well known producer of such coils is Cadwell, which produces a variety of different models. One of the goals of the present inventors has been to provide magnetic stimulator devices for use in a variety of applications, which are improvements over the devices previously used in the art. In our prior issued U.S. Pat. No. 5,725,471, filed Nov. 28, 1994 and issued Mar. 10, 1998, which is the parent to the present application (the disclosure of which is fully incorporated herein by reference), a variety of such devices were disclosed for the use in peripheral nerve stimulation. Accordingly, it is an object of the present inventors herein to provide further devices for use in central nervous system stimulation in general, and transcranial brain stimulation in particular.
The Treatment of Depression
Transcranial magnetic stimulation is known to non-invasively alter the function of the cerebral cortex. (See e.g., George M S, Wassermann E M, Post R M, Transcranial magnetic stimulation: A neuropsychiatric tool for the 21 st century, J. Neuropsychiatry, 1996; 8: 373-382, the disclosure of which is fully incorporated herein by reference). The magnetic fields used are generally generated by large, rapidly-changing currents passing through a wire coil on the scalp. Two recent studies have suggested that rapid rate transcranial magnetic stimulation (rTMS) may be used for exploring the functional neuroanatomy of emotions: healthy volunteers who received left pre-frontal stimulation reported an increase in self-rated sadness, while, in contrast, right pre-frontal stimulation caused an increase in happiness. (See, Pascual-Leone A., Catala M D, Pascual A P, Lateralized effect of rapid rate transcranial magnetic stimulation of the prefrontal cortex on mood, Neurology, 1996; 46: 499-502; and, George M S, Wasserman E M, Williams W., et al., Changes in mood and hormone levels after rapid-rate transcranial magnetic stimulation of the prefrontal cortex, J. Neuropsychiatry Clin. Neurosci. 1996; 8: 172-180, the disclosures of which are fully incorporated herein by reference.)
Other reports have begun to delineate the therapeutic use of rTMS in depression. The earliest such studies used round, non-focal coils centered at the cranial vertex, with stimulation rates well under 1 Hertz (Hz). Results were promising but not always statistically significant. (See, Hoflich G., Kasper S. Hufnagel A. et al., Application of transcranial magnetic stimulation in treatment of drug-resistant major depression: a report of two cases, Human Psychopharmacology, 1993; 8: 361-365; Grisaru N., Yarovslavsky U., Abarbanel J., et al., Transcranial magnetic stimulation in depression and schizophrenia, Eur. Neuropsychopharmacol. 1994; 4: 287-288; and, Kilbinger H M, Hofllich G., Hufnagel A., et al., Transcranial magnetic stimulation (TMS) in the treatment of major depression: A pilot study, Human Psychopharmacology, 1995; 10: 305-310, the disclosures of which are fully incorporated herein by reference.)
Subsequently, George et al., described striking improvement in some depressed patients from treatment with rTMS over the left pre-frontal cortex. (See, George M S, Wasserman E M, Williams W A, et al., Daily repetitive transcranial magnetic stimulation (rTMS) improves mood in depression, NeuroReport, 1995; 6: 1853-1856; and, George M S, Wasserman E M, Williams W E, Kimbrell T A, Little J T, Hallett M., Post R M, Daily left prefrontal rTMS improves mood in outpatient depression: a double blind placebo-controlled crossover trial, Am. J. Psychaitry, 1997 (in press), the disclosures of which are fully incorporated herein by reference). The largest such study to date was reported by Pascual-Leone et al., who used a five-month double blind placebo-controlled cross over design with five different treatment conditions. (See, Pascual-Leone A., Rubio B., Pallardo F. Catala M D, Rapid-rate transcranial magnetic stimulation of left dorsolateral prefrontal cortex in drug-resistant depression, The Lancet, 1996; 348: 233-237, the disclosure of which is fully incorporated herein by reference.) Left pre-frontal rTMS was uniquely effective in 11 of 17 young (less than 60 years of age) psychotically depressed and medication resistant patients.
Accordingly, further to the work which has been done thus far in this field, it is also a goal of the present inventors to provide improved apparatus and methods for transcranial magnetic stimulation, and for the treatment of depression using such stimulation, as described more fully hereafter.
The Localization of Speech Arrest
With respect to the methods previously used for the localization of speech arrest, active localization of language function has traditionally been possible only with invasive procedures. The dominant hemisphere can be determined using the intracarotid amobarbital or Wada test. Cortical areas critical to language can be mapped using electrocorticography in the operating room, (See e.g. Penfield, 1950, cited below) or extra-operatively through electrode grids implanted in the subdural space. (See e.g. Lesser, 1987, cited below). The Wada test and electrocorticography have contributed greatly to our current understanding of language organization. However, because of their complexity and potential morbidity, these techniques are confined almost entirely to patients undergoing surgery for intractable epilepsy.
In the past decade, positron emission tomography and functional magnetic resonance imaging have shown promising results for language localization. But these newer imaging technologies requite complex and expensive equipment, and have other limitations in the form of poor temporal resolution or a restricted test environment. The correlation between the degree of metabolic change in different brain areas and their importance for a given cognitive task remains unknown. (See e.g., Ojemann, cited below).
At least four groups have reported lateralized speech arrest using rapid-rate transcranial magnetic brain stimulation (rTMS) in epilepsy patients. (See e.g., Pascual-Leone, 1991, Michelucci, 1994, Jennum, 1994, and Epstein, 1996, cited below). The results showed a high correlation with the Wada test, but sensitivity in the two largest series was only 50-67% (See, e.g., Jennum, 1994, and Michelucci, 1994, cited below). Most of these studies used large circular magnetic coils, along with stimulus parameters that may carry a risk of inducing seizures. (See, e.g. Pascual-Leone, 1993, cited below). Thus, the initial rTMS techniques were not optimal for detailed localization or for studies involving normal subjects.
Consequently, further to the work which has previously been done, it is also a goal of the present inventors to provide improved apparatus and methods for localization and characterization of brain function. As described hereafter, we recently described modifications of rTMS that produce lateralized speech arrest with reduced discomfort, a repetition rate as low as four Hertz, and a combination of stimulus parameters that comply with recent recommendations for safety in rTMS (See also, Epstein C M, Lah J J, Meador K, Weissman J D, Gaitain L E, Dihenia B, Optimum stimulus parameters for lateralized suppression of speech with magnetic brain stimulation, Neurology, 47: 1590-1593 (December 1996), the disclosure of which is fully incorporated herein by reference). The technique is useful for detailed studies of magnetic speech arrest in normal individuals.
An object of the present invention is to provide an improved apparatus for transcranial magnetic brain stimulation.
A further object of the present invention is to provide an improved method for characterizing and localizing brain function.
A further object of the present invention is to provide an improved method for characterizing and localizing speech arrest.
A further object of the present invention is to provide an improved method for treatment of depression.
As disclosed more fully hereafter, an apparatus is described for use in transcranial brain stimulation. The apparatus is designed to produce a focussed magnetic field which can be directed at sites on the brain of interest or importance. The device consists of at least one, but preferably four magnetic cores. The cores are preferably constructed of a ferromagnetic material. The cores can have an outer diameter between approximately 2 and 7 inches, and an inner diameter between approximately 0.2 and 1.5 inches. The material of the cores has a magnetic saturation of at least 0.5 Tesla, and preferably at least 1.5 Tesla, or even 2.0 Tesla or higher. In the preferred embodiment, the core conforms in construction to the shape of the head to improve its efficacy. A visualization and location port is included to assist with the precision placement of the core on the head, and to assist with exact marking of the stimulator""s position.
Using the described apparatus and method, an optimized technique for transcranial magnetic brain stimulation is provided which has a variety of useful applications. For example, the present apparatus and method can be employed for brain stimulation in a therapeutic protocol for the treatment of depression. In addition, the apparatus and method can be used for the localization and characterization of brain function. For example, detailed anatomic localization of speech arrest and effects on other language function can be studied. The invention therefore provides devices and methods for non-invasive stimulation and treatment of the brain, and for studying and characterizing brain function, which are improvements over the procedures of the prior art.
Using the apparatus and technique on four normal righthanded volunteers, to study speech arrest for example, it was determined that all were dominant for magnetic speech arrest over the left hemisphere. While subjects counted aloud, points of speech arrest were mapped on a one-centimeter grid over the left frontal region. Compound motor action potentials from muscles in the right face and hand were mapped onto the same grid. Subjects were then tested in reading, writing, comprehension, repetition, naming, spontaneous singing, and oral praxis during magnetic stimulation. Finally, mean positions for speech arrest and muscle activation were identified on three dimensional MRI.
All of the subjects tested using the present technique had complete, lateralized arrest of counting and reading with magnet stimulation over the left posterior-inferior frontal region. Writing with the dominant hand, comprehension, repetition, visual confrontation naming, oral praxis, and singing were relatively or entirely spared, with rare aphasic errors. In two subjects, melody was abolished from singing during stimulation over the right hemisphere. In all four subjects, the region of speech arrest was highly congruous with the region where stimulation produced movement of the right face, and overlay the caudal portion of the precentral gyrus. This constellation of behavioral and anatomic findings is similar to that found in aphemia, and supports a modular theory of language organization in the left hemisphere.
In patients with refractory depression, the stimulator of the present invention was used to stimulate the brain with magnetic pulses using rapid rate transcranial magnetic stimulation over the left prefrontal region of the brain. In a group of 32 patients aged 22-64, all Hamilton Depression (Ham-D) scores were above 20 prior to treatment. Twenty-eight (28) patients completed treatment: average Ham-D scores fell from thirty one (31) to fifteen (15), and individual scores fell to less than ten (10) in fourteen (14) out of twenty-eight (28) of the subjects. Sixteen (16) out of the twenty eight (28) patients were clear responders to rTMS. Two enrollees dropped out because of pain during stimulation, and three had possible adverse effects during the course of treatment that we were unable to connect causally with rTMS. Thus, it was found that rTMS could be used as a simple and effective treatment for many patients with refractory depression who would otherwise be candidates for ECT.